There is a continuing need to provide new agents for the control of parasitic infestations that present a threat to human and animal health. In particular, new agents are needed to manage endoparasitic infestations in animals due to the increasing prevalence of parasites, and in particular nematodes, that are resistant to many of the agents currently approved for this indication. The compounds currently available for endoparasitic treatment of animals do not always demonstrate good activity, good speed of action, or a long duration of action, and many are no longer efficacious as a result of genetic resistance. The gamma-carbolines of the instant invention have been shown to impart antiparasitic activity, particularly endoparasitic activity.
Beta-carboline derivatives have been described in publications WO2002/088123 and WO2011/038163. These β-derivatives reportedly modulate aminergic G protein-coupled receptors, 5-HT6 receptors, and cGMP-specific PDE receptors for the treatment of cognitive disorders, cardiovascular disorders, erectile dysfunction, and other neurotransmitter mediated disorders, not parasiticidal activity. Publication WO2003/014118 generically describes hexahydro- and tetrahydro-1H-pyrido[4,3-b]indoles as 5-HT ligands capable of treating diseases modulated by 5-HT6, for example, conditions which originate in the central nervous system (pain, dementia, neurodegenerative disorders, hypertension, sleeping, and others). However, this application publication does not describe or exemplify any piperidine substituted derivatives or amide substitutions (urea) of the indole moiety which were shown to impart nematocidal activity to the compounds of the instant invention. Other antiparasitic indoles have been described in application publication WO2005/061500, WO2005/058897, and WO2013/017678, however, these are all spiroindoline derivatives. The prior art citations do not exemplify the gamma-carboline derivatives of the instant invention, or processes of manufacturing the same, nor does the prior art indicate that such compounds would be useful against a spectrum of parasitic species, particularly endoparasites.
Despite the availability of effective, broad spectrum antiparasitic agents, there remains a need for a safer, convenient, efficacious, and environmentally friendly product(s) that will overcome the ever-present threat of resistance development.
The present invention overcomes one or more of the various disadvantages of, or improves upon, the properties of existing compounds. In particular the present invention develops new gamma-carboline derivatives that demonstrate such antiparasitic properties.